Influenza A infection causes annual substantial morbidity and mortality worldwide, particularly for infants, the elderly, and the immuncompromised. Current vaccines, such as the parenterally administered trivalent inactivated vaccine (TIV) are administered either unadjuvanted or adjuvanted with aluminum hydroxide (alum). The efficacy of these vaccines is highly dependent on close matching of the hemagglutinin (HA) and neuraminidase (NA) surface proteins of the vaccine with currently circulating virus. Should neutralizing antibody fail to prevent infection of the respiratory tract, subsequent clearance of viral infection is mainly dependent on T cells, particularly cytolytic T lymphocytes (CTL) of the CD8+ T-cell subset. Juvaris BioTherapeutics is developing and characterizing a unique adjuvant that is particularly promising for vaccines that induce both high levels of antibody and T-cell immunity, including CTL. The adjuvant is based on a cationic lipid carrier and non-coding DNA complex (CLDC). Inclusion of protein antigens with CLDC results in an extremely robust humoral and CD4+ and CD8+ T-cell response. The unique aspect of the CLDC adjuvant is that it functions both as a delivery system that targets associated antigens to antigen presenting cells via the liposome component and an immunostimulatory adjuvant via the plasmid DNA. The final product resulting from this proposal is the completion of pre-clinical evaluation and development of the CLDC product for use as an adjuvant in viral vaccines and specifically for influenza. The product development strategy for the CLDC adjuvant in influenza is focused on the exploitation of the near-term opportunity of adjuvanting currently approved vaccines (in the U.S. and abroad) while recognizing the potential of recombinant vaccine approaches currently being evaluated. The specific goals of this proposal are to: 1) Establish limits on adjuvant and vaccine preparation and storage; 2) Optimization of dose; 3) Comparison of the magnitude and durability of the immune response following CLDC/Ag vaccination with existing adjuvants or no adjuvants; 4) Determine mechanism of action of the adjuvant in inducing adaptive immunity in mouse and non-human primate; 5) extent of heterosubtypic protection with CLDC adjuvanted monovalent split vaccines, which will be prepared in house, or monovalent whole inactivated vaccine virus. There is significant evidence that heterosubtypic immunity may follow natural infection and, to a lesser extent, current vaccination strategies. Such immunity will likely be markedly enhanced using CLDC adjuvanted vaccines, but a formal demonstration of this in mice and non-human primates is required before vaccine strategies invoking this mechanism can be clinically tested and adopted for general application.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
6U01AI074512-06
Application #
8411922
Study Section
Special Emphasis Panel (ZAI1-CCH-M (M1))
Program Officer
Salomon, Rachelle
Project Start
2007-08-01
Project End
2013-07-31
Budget Start
2011-10-02
Budget End
2013-07-31
Support Year
6
Fiscal Year
2011
Total Cost
$1,438,772
Indirect Cost
Name
Colby Pharmaceutical Company
Department
Type
DUNS #
611495974
City
San Jose
State
CA
Country
United States
Zip Code
95138
Carroll, Timothy D; Jegaskanda, Sinthujan; Matzinger, Shannon R et al. (2018) A Lipid/DNA Adjuvant-Inactivated Influenza Virus Vaccine Protects Rhesus Macaques From Uncontrolled Virus Replication After Heterosubtypic Influenza A Virus Challenge. J Infect Dis 218:856-867
Liu, Feng; Sun, Xiangjie; Fairman, Jeffery et al. (2016) A cationic liposome-DNA complexes adjuvant (JVRS-100) enhances the immunogenicity and cross-protective efficacy of pre-pandemic influenza A (H5N1) vaccine in ferrets. Virology 492:197-203
Carroll, Timothy D; Matzinger, Shannon R; Barry, Peter A et al. (2014) Efficacy of influenza vaccination of elderly rhesus macaques is dramatically improved by addition of a cationic lipid/DNA adjuvant. J Infect Dis 209:24-33
Dong, Libo; Liu, Feng; Fairman, Jeffery et al. (2012) Cationic liposome-DNA complexes (CLDC) adjuvant enhances the immunogenicity and cross-protective efficacy of a pre-pandemic influenza A H5N1 vaccine in mice. Vaccine 30:254-64
Hong, David K; Tremoulet, Adriana H; Burns, Jane C et al. (2011) Cross-reactive neutralizing antibody against pandemic 2009 H1N1 influenza a virus in intravenous immunoglobulin preparations. Pediatr Infect Dis J 30:67-9
Carroll, Timothy D; Matzinger, Shannon R; Barro, Mario et al. (2011) Alphavirus replicon-based adjuvants enhance the immunogenicity and effectiveness of Fluzone ® in rhesus macaques. Vaccine 29:931-40
O'Gorman, William E; Sampath, Padma; Simonds, Erin F et al. (2010) Alternate mechanisms of initial pattern recognition drive differential immune responses to related poxviruses. Cell Host Microbe 8:174-85
Hong, David K; Chang, Stella; Botham, Crystal M et al. (2010) Cationic lipid/DNA complex-adjuvanted influenza A virus vaccination induces robust cross-protective immunity. J Virol 84:12691-702
Lay, Marla; Callejo, Bernadette; Chang, Stella et al. (2009) Cationic lipid/DNA complexes (JVRS-100) combined with influenza vaccine (Fluzone) increases antibody response, cellular immunity, and antigenically drifted protection. Vaccine 27:3811-20